First genome-wide association study of non-severe malaria in two birth cohorts in Benin: hints towards the involvement of the STAT3 pathway.

Recent research efforts to identify genes involved in the susceptibility to P. falciparum malaria have focused on severe forms of malaria, with several genome-wide association studies (GWAS) and multi-center analyses published this past decade. Here we present the first GWAS performed on mild malaria susceptibility in young children, designed to identify genetic variants involved in innate immunity or innate resistance mechanisms. Two cohorts of infants from southern Benin (525 and 250 individuals respectively), used as discovery and replication cohorts, were closely followed from birth to 18-24 months of age, with an assessment of a space- and time-dependent risk of exposure to vector bites. GWAS was performed on 15.5 million genotyped and imputed variants, with the susceptibility of infants to mild malaria attacks and to malaria infections as a whole (both symptomatic and asymptomatic). Infant susceptibility to malaria was assessed by considering all malaria events occurring during the follow-up using a Cox-model for recurrent events. We found strong statistical support for a role of PTPRT, a tyrosine phosphatase receptors involved in STAT3 pathway, with the protection against both mild malaria attacks and malaria infections (p=9.70x10-8 and p=1.78x10-7 respectively in the discovery cohort, and both p